Dipeptidyl peptidase IV is a membrane serine protease that is present in many human tissues and involved in numerous pathologies.
In particular, it has been shown that DPP IV is responsible for the inactivation of GLP-1 (glucagon-like peptide-1). GLP-1 is an important stimulator of the secretion of insulin in the pancreas and accordingly has a direct beneficial effect on the level of glucose in the blood.
Inhibition of DPP IV accordingly constitutes an extremely promising approach in the treatment of glucose intolerance and of disorders associated with hyperglycaemia, such as, for example, non-insulin-dependent diabetes (type II diabetes) or obesity.
DPP IV inhibitors have already been described in the literature, for example amide compounds in Patent Application EP 0 490 379 and in the journal Adv. Exp. Med. Biol. 1997, 421, 157-160, and carbamate compounds in Patent Application DE 19826972.
Moreover, xcex1-amino acid compounds, analogues of arginine, have been described in Patent Application WO 96/27593 as inhibitors of NO-synthase, for use, as such, in the treatment of pathologies of the central and peripheral nervous systems, pathologies of dysfunctions of the gastrointestinal and urinary systems, and pathologies associated with the cardiovascular or bronchopulmonary system.
The compounds of the invention have dipeptidyl peptidase IV-inhibiting properties, which thus makes them especially useful in the treatment of glucose intolerance and disorders associated with hyperglycaemia.
More especially, the present invention relates to compounds of formula (I): 
wherein: 
represents a 5-membered nitrogen-containing heterocycle optionally substituted by a cyano group,
Ak represents a linear or branched (C1-C6)alkylene chain,
X represents a single bond or a phenylene group,
R1 and R2, which may be identical or different, each represent a hydrogen atom or a linear or branched (C1-C6)alkyl group,
Y represents NR4 or CHxe2x80x94NO2,
R4 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group,
R3 represents:
a group selected from linear or branched (C1-C6)alkyl, nitro and cyano, when Y represents CHxe2x80x94NO2, or
a group selected from nitro and cyano, when Y represents NR4,
their tautomers when they exist, their optical isomers, and addition salts thereof with a pharmaceutically acceptable acid,
with the exclusion of compounds wherein, simultaneously, 
represents an unsubstituted 5-membered nitrogen-containing heterocycle, Ak represents the group xe2x80x94(CH2)3xe2x80x94, X represents a single bond, Y represents NH and R3 represents the nitro group.
Among the pharmaceutically acceptable acids, there may be mentioned by way of non-limiting example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulphonic acid, camphoric acid, oxalic acid, etc.
xe2x80x9c5-membered nitrogen-containing heterocyclexe2x80x9d is understood to mean a 5-membered saturated monocyclic group containing one, two or three hetero atoms, one of which hetero atoms is the nitrogen atom, and any additional hetero atoms present are selected from the atoms oxygen, nitrogen and sulphur.
The preferred 5-membered nitrogen-containing heterocycles are the groups pyrrolidinyl and thiazolidinyl.
The compounds of formula (I) wherein R2 represents a hydrogen atom exist in two tautomeric forms represented by the formulae (Ia) and (Ib): 
which both form an integral part of the invention.
The compounds of formula (I) wherein R3 represents a hydrogen atom exist in two tautomeric forms represented by the formulae (Ic) and (Id): 
which both form an integral part of the invention.
The preferred compounds of formula (I) are those wherein 
represents a 1-pyrrolidinyl group optionally substituted by a cyano group, or a 1,3-thiazolidin-3-yl group optionally substituted by a cyano group.
The preferred compounds of formula (I) are those wherein the configuration xcex1 to the amide function is (S).
An advantageous aspect of the invention relates to compounds of formula (I) wherein Ak represents the group (CH2)4.
Another advantageous aspect of the invention relates to compounds of formula (I) wherein 
represents a 1-pyrrolidinyl group substituted by a cyano group, or a 1,3-thiazolidin-3-yl group substituted by a cyano group, and Ak represents the group (CH2)3.
A further advantageous aspect of the invention relates to compounds of formula (I) wherein X represents a single bond.
A further advantageous aspect of the invention relates to compounds of formula (I) wherein Y represents a group NR4, wherein R4 represents a hydrogen atom or a linear or branched (C1-C6)alkyl group.
A further advantageous aspect of the invention relates to compounds of formula (I) wherein R3 represents the nitro group.
Among the preferred compounds of the invention, there may be mentioned more especially:
N-{(4S)-4-amino-5-[(2S)-2-cyano-1-pyrrolidinyl]-5-oxopentyl}-Nxe2x80x2-nitroguanidine, its tautomers, optical isomers, and addition salts thereof with a pharmaceutically acceptable acid,
N-{(5S)-5-amino-6-[(2S)-2-cyano-1-pyrrolidinyl]-6-oxohexyl}-Nxe2x80x2-nitroguanidine, its tautomers, optical isomers, and addition salts thereof with a pharmaceutically acceptable acid, and
N-{(5S)-5-amino-6-(1,3-thiazolidin-3-yl)-6-oxohexyl}-Nxe2x80x2-nitroguanidine, its tautomers, optical isomers, and addition salts thereof with a pharmaceutically acceptable acid.
The invention relates also to a process for the preparation of compounds of formula (I), characterised in that a compound of formula (II): 
wherein Ak and X are as defined for formula (I), P1 represents an amino-function-protecting group, and P2 represents an amino-function-protecting group other than P1,
is reacted with a compound of formula (III): 
wherein 
is as defined for formula (I),
under conventional peptide coupling conditions, to yield, after deprotection, a compound of formula (IV), 
wherein 
P1, Ak and X are as defined hereinbefore,
which is then converted, by conventional organic chemistry reactions, followed by a deprotection reaction, to a compound of formula (I),
which is purified, if necessary, according to a conventional purification technique, separated, if desired, into its optical isomers according to a conventional separation technique, and converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid.
The compounds of formula (Ie), a particular case of the compounds of formula (I): 
wherein 
R1, Ak and X are as defined for formula (I), can also be obtained starting from the compound of formula (V): 
wherein P1, Ak and X are as defined hereinbefore, which is reacted with a compound of formula (III), under conventional peptide coupling conditions,
to yield, after deprotection where necessary, a compound of formula (Ie), which is purified, if necessary, according to a conventional purification technique, separated, if desired, into its optical isomers according to a conventional separation technique, and converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid.
The compounds of the present invention, in addition to being new, have pharmacologically valuable properties. They have dipeptidyl peptidase IV-inhibiting properties which make them useful in the treatment of glucose intolerance and of disorders associated with hyperglycaemia, such as type II diabetes or obesity.
The invention relates also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I) with one or more suitable inert, non-toxic excipients. Among the pharmaceutical compositions according to the invention, there may be mentioned more especially those that are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous) or nasal administration, tablets or dragxc3xa9es, sublingual tablets, gelatin capsules, lozenges, suppositories, injectable preparations, drinkable suspensions, etc.
The useful dosage can be adapted according to the nature and severity of the disorder, the route of administration and the age and weight of the patient and any associated treatments. The dosage varies from 0.5 mg to 2 g per 24 hours in one or more administrations.
The following Examples illustrate the invention and do not limit it in any way.
The starting materials used are known products or are prepared according to known procedures.
The structures of the compounds described in the Examples were determined according to the usual spectrometric techniques (infrared, NMR, mass spectrometry).
The expression xe2x80x9ccompound of configuration (2xcex1) or (2xcex2)xe2x80x9d is understood to mean a compound selected from the compounds of absolute configurations (2R) and (2S), it being understood that when compound (2xcex1) represents the compound of absolute configuration (2R), then compound (2xcex2) represents the compound (2S).